c-Abl is a ubiquitously expressed nonreceptor tyrosine kinase that is localized to the nucleus and cytoplasm. The function of c-Abl has been unknown. Recent studies have demonstrated that nuclear c-Abl is activated by DNA-damaging agents. Other work from my laboratory has shown that DNA damage induces binding of c-Abl to the p53 tumor suppressor protein. Moreover, c-Abl regulates the G1 growth arrest response to DNA damage by a p53-dependent, p21-independent mechanism. Cells expressing a dominant negative, kinase inactive c-Abl exhibit defects in the G1 growth arrest response. Similar findings have been obtained in c-Abl-deficient cells. My hypothesis is that c-Abl is an important mediator of the genotoxic stress response and that this kinase contributes to the regulation of cell fate. Few insights are available regarding the mechanisms responsible for regulation of the cell cycle in response to DNA damage. The proposed work will explore my finding that c-Abl regulates the G1 arrest response by a p21-independent mechanism. The proposed work will also study the interaction of c-Abl with a complex involving p53 and p300/CBP. Other findings indicate that c-Abl exhibits a pro-apoptotic function in the response to DNA damage. Whereas DNA damage is associated with arrest of cells in G1 phase, my hypothesis is that c-Abl coordinates this response, and in the event of irreparable DNA damage, contributes to the induction of apoptosis. The proposed studies will explore the mechanisms responsible for involvement of c-Abl in DNA damage-induced apoptosis. The findings obtained from the proposed work should represent a paradigm for studies on cell fate, that is survival or induction of apoptosis, in the cellular response to genotoxic stress. The Specific Aims are: 1) to determine the functional interactions of c-Abl and p53 in the G1 arrest response to DNA damage; and 2) to study the pro-apoptotic function of c-Abl in the response to DNA damage.